Abstract Weight gain and metabolic dysfunction are common, serious side effects of many psychiatric medications, especially antipsychotic drugs. These effects are amplified in children and can severely compromise physical health and interfere with psychiatric treatment. While the mechanism of antipsychotic-induced weight gain (AIWG) is poorly understood, studies in rodents have argued for a central role of gut microbes. Our team showed a similar effect in children taking the antipsychotic risperidone (RSP). We further hypothesized that gut microbes could impact weight and metabolism by altering bile acid (BA) signaling. Primary BAs made in the liver are converted to secondary BAs by gut bacteria. These two types of BAs have opposing effects on the liver farnesoid X receptor (FXR), involved in metabolism and energy balance. In support of this model, we determined that RSP exposure in youth with autism resulted in plasma BA elevations. The BA balance was distinct between those who gained weight on RSP and those who did not. Higher primary BAs favored weight gain, while higher secondary BAs were protective. This pattern was repeated in a small independent sample of children taking RSP and interestingly, in children taking selective serotonin reuptake inhibitors (SSRIs). Therefore, this proposal seeks to test this novel gut microbe-BA model of AIWG in children started on RSP by their physician for any mental illness. We will follow 60 children during the first 8 weeks of RSP treatment and collect blood and stool to measure BAs and gut microbes respectively. In those who gain weight with RSP treatment compared to those who do not, we predict a decrease in the abundance of gut bacteria capable of converting primary to secondary BAs and a resultant shift in the BA pool toward primary BAs. If proven, this model could guide clinical interventions to prevent metabolic side effects, as several potential treatments impacting this system are currently available for other uses. Additionally, this mechanism may apply more globally to other drug classes and possibly to obesity and metabolic dysfunction in general.